Oral thin film

ABSTRACT

Described is an oral thin film comprising at least one matrix layer, wherein the at least one matrix layer comprises at least one pharmaceutically active agent, at least one polyvinyl alcohol and at least one polyvinyl alcohol-polyethylene glycol graft copolymer, a method for producing same, and use thereof as a medicament.

The present invention relates to an oral thin film containing at leastone pharmaceutically active agent, a method for producing same, and theuse of such an oral thin film as a medicament, especially in thetreatment of pain and/or depression.

Oral thin films are thin films containing at least one pharmaceuticallyactive agent that are placed directly in the oral cavity or against theoral mucosa and dissolve or macerate there and in so doing deliver theactive agent. These films are, especially, thin active agent-containingpolymer-based films which, when applied to a mucous membrane, especiallythe oral mucosa, can deliver the active agent directly into same. Thevery good blood supply to the oral mucosa ensures a rapid transfer ofthe active agent into the bloodstream. This dosage system has theadvantage that the active agent is resorbed for the most part by themucous membrane, thus avoiding the first-pass effect, which occurs inthe case of the conventional dosage form of an active agent in tabletform. The active agent may be dissolved, emulsified or dispersed in thefilm.

As explained in greater detail further below, the oral thin filmaccording to the invention preferably contains ketamine aspharmaceutically active agent and is preferably used for the treatmentor prevention of pain.

The repositioning of ketamine from a medicinal perspective as ananalgesic indicates the possibility of a new pain treatment option.Ketamine has proven to be effective in the treatment of moderate tosevere pain and represents a useful alternative to opioid analgesia.Ketamine has also been found to reduce hyperalgesia (increasedsensitivity to feeling pain), which occurs in many pain conditions, morespecifically also by the long-term ingestion of opioids. In combinationwith opioids, ketamine also has the effect of reducing the dosage amountof opioids, which is necessary for achieving this analgesia.

The NMDA receptor antagonism of ketamine offers a “non-opioid” treatmentoption for the treatment of pain, which satisfies the unfulfilledrequirements of the current therapy (for example reduced severe sideeffects in conjunction with opioids). (S)-ketamine, in comparison to theracemate, has approximately twice the analgesic effect as well as ananti-depressive effect. In contrast to opioids, the lethal dose of(S)-ketamine is very high (lethal dose averaged at 4.2 g/70 kg, forexample lethal dose of fentanyl 2 mg/70 kg, oxycodone 40 mg/70 kg).

When administering some pharmaceutically active agents, high activeagent loads of the oral thin film are desirable. A high active agentload in oral thin films is a known problem, since this can lead tobrittle films or can directly prevent a film formation of the containedpolymers. In order to achieve this nevertheless, large oral thin filmsor oral thin films with very high layer thicknesses are generallyrequired. Large or thick oral thin films have the disadvantage that theycause problems with the application and may cause the patient toexperience a sensation of a foreign body and may lead to long dissolvingtimes.

Depending on the application, however, long disintegration times areundesirable.

In addition, known oral thin films with high active agent load have thedisadvantage that the maximum area density and thus the amount ofcontained pharmaceutically active agent is determined by the drying ofthe oral thin film during production thereof. The greater is the areadensity of the oral thin film, the more pharmaceutically active agentmay be contained therein, however, the drying time of the oral thin filmis extended, as a result, to a time that is no longer economical, and inaddition the active agent may be distributed inhomogeneously in the oralthin film.

BRIEF DESCRIPTION

The aim of the present invention lies in overcoming the above-mentioneddisadvantages of the prior art. Especially, the aim of the presentinvention lies in providing an oral thin film for administering a highamount of at least one pharmaceutically active agent, wherein the oralthin film has an acceptable disintegration time, and wherein thepharmaceutically active agent is distributed relatively homogeneously inthe oral thin film. Furthermore, the oral thin film will have apreferably pleasant and soft texture and therefore preferably will nottrigger a sensation of a foreign body for the patient. The oral thinfilm according to the invention will also allow the greatest possiblebioavailability of, for example, more than 10% or more than 20% or morethan 30% or more than 40% or more than 50% or more than 60% or more than70% or more than 80% or more than 90% of the pharmaceutically activeagent.

The oral thin film according to the invention preferably has abioavailability of 20 to 30% of the pharmaceutically active agent.

In addition, the oral thin film according to the invention will bedesigned such that approximately 40 to 60% of the containedpharmaceutically active agent can be released within the first minutefollowing application, or approximately 75 to 90% of the containedpharmaceutically active agent can be released after the first twominutes following application.

In addition, once the oral thin film has been administered, minimal sideeffects will occur, especially minimal psychedelic effects(psychological and psychomimetic side effects).

In addition, it will be possible to produce the oral thin film as easilyand economically as possible.

Especially, the at least one pharmaceutically active agent will compriseketamine.

The above aim is addressed by an oral thin film according to claim 1,which has at least one matrix layer, wherein the at least one matrixlayer comprises at least one pharmaceutically active agent, especiallyketamine, at least one polyvinyl alcohol, and at least one polyvinylalcohol-polyethylene glycol graft copolymer.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphical depiction of the results of a release study forFormulation 15;

FIGS. 2A-I are graphical depictions showing a reduction in pressure,electrical and heat pain;

FIGS. 3-5 show the plasma level of the metabolite (S)-norketamine arehigher following administration of an OTF as compared tointravenous-administration of 20 mg (S)-ketamine;

FIGS. 6-8 show the plasma level of the metabolite (S)-hydroxynorketamineare higher following administration of an OTF as compared to intravenousadministration of 20 mg (S)-ketamine;

FIGS. 9-11 show the plasma levels of ketamine are higher for intravenousadministration than following administration of an OTF;

FIGS. 12-15 show the data relating to the observed psychedelic effects(phychological and psychomimetic side effects) according to the Bowdlequestionnaire;

FIGS. 16-31 show the data relating response to the Bond and Ladequestionnaire; and

FIG. 32 shows the results of the permeation study of Example 5.

DETAILED DESCRIPTION

It has been found that a polyvinyl alcohol-polyethylene glycol graftcopolymer can absorb a high amount of active agent.

This has also been observed already in polyvinyl alcohols, where thiseffect is even more pronounced in part. Films based on polyvinyl alcoholalone, however, are hard and thus have a texture that is unpleasant forthe patient.

Films based on a polyvinyl alcohol-polyethylene glycol graft copolymeralone, by contrast, have a softer texture since the polymer itself formssofter films. These films, however, are not quite so stable.

Due to the mixture of a polyvinyl alcohol-polyethylene glycol graftcopolymer and a polyvinyl alcohol, it has been possible to achieve afilm which, with a high active agent load, has the soft texture of apolyvinyl alcohol-polyethylene glycol graft copolymer film alongside astability approaching that of a polyvinyl alcohol film.

The polyvinyl alcohol-polyethylene glycol graft copolymer preferablyforms the basic structure and decisively determines the film properties,and the polyvinyl alcohol acts as an additional stabiliser.

A high active agent load with layer thicknesses and film sizes inacceptable ranges can thus be achieved. The dissolving times also lie inan acceptable range, the acceptable range preferably comprising valuesof less than 1 min. In addition, such an oral thin film is agreeable tothe patient and can be produced easily and economically.

Preferred embodiments are described in the dependent claims.

In the present document, the word “comprising” can also mean “consistingof”.

The oral thin film according to the invention has at least one matrixlayer, wherein the at least one matrix layer comprises at least onepharmaceutically active agent, especially ketamine, at least onepolyvinyl alcohol, and at least one polyvinyl alcohol-polyethyleneglycol graft copolymer.

The at least one pharmaceutically active agent is not subject inprinciple to any limitation, but is preferably selected from allpharmaceutically active agents that are suitable for oral and/ortransmucosal application.

According to the present invention, all pharmaceutically acceptablesalts and solvates of the particular pharmaceutically active agent arealso subsumed under the pharmaceutically active agent.

Active agents are preferably selected from the group comprising theactive agent classes of analgesics, hormones, hypnotics, sedatives,antiepiletics, analeptics, psychoneurotropic drugs, neuro-muscleblockers, antspasmodics, antihistamines, antiallergics, cardiotonics,antiarrhythmics, diuretics, hypotensives, vasopressors, antidepressants,antitussives, expectorants, thyroid hormones, sexual hormones,antidiabetics, antitumour active agents, antibiotics, chemotherapeuticsand narcotics, however, this group is not conclusive.

Polyvinyl alcohols (abbreviated to PVA or PVAL, sometimes also PVOH) arepolymers of the general structure

which can also contain small amounts (approximately 2%) of structuralunits of the type

They belong to the group of vinyl polymers.

Commercially customary polyvinyl alcohols, which are offered in the formof white-yellow powder or granules, generally have a degree ofhydrolysis of 98 to 99 or 87 to 89 mol %, that is to say also contain aresidual content of acetyl groups. The polyvinyl alcohols arecharacterised by the manufacturer by a specification of the degree ofpolymerisation of the starting polymers or the mean molecular weight,the degree of hydrolysis, the saponification number or the solutionviscosity.

Graft copolymers are branched polymers that contain different monomerunits in the main chain and the branched chain.

The term “graft copolymers” is a common term.

The polyvinyl alcohol-polyethylene glycol graft copolymer provided herepreferably has a main chain, comprising polyethylene glycol, onto whichthe polyvinyl alcohol units are grafted.

The oral thin film according to the invention is preferably alsocharacterised in that the at least one pharmaceutically active agentcomprises ketamine, preferably (S)-ketamine or a pharmaceuticallyacceptable salt thereof.

The oral thin film according to the invention in another embodiment ispreferably characterised in that the at least one pharmaceuticallyactive agent comprises ketamine, preferably R-ketamine or apharmaceutically acceptable salt thereof.

Ketamine is preferably provided in the form of an HCl salt or in theform of a free base.

In the present case, ketamine is understood to mean(S)-(±)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one,(R)-(±)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one, and theracemate (RS)-(±)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one.

After administration, ketamine is metabolised to norketamine,hydroxynorketamine and further substances.

Both (S)-ketamine and R-ketamine as well as a racemic mixture of thesetwo can be contained in the matrix layer of the oral thin film accordingto the invention. However, (S)-ketamine in the form of a free base or apharmaceutically acceptable salt thereof, especially (S)-ketamine HCl,is especially preferably present as a single stereoisomer of ketamine,since the analgesic and anaesthetic potency of (S)-ketamine isapproximately three times higher than that of the (R) form.

The oral thin film according to the invention is also preferablycharacterised in that the at least one pharmaceutically active agent,preferably ketamine, is provided in the matrix layer in an amount of 45to 70 wt. %, preferably of 50 to 65 wt. %, or of 55 to 65 wt. %, or of55 to 60 wt. %, or of 60 to 65 wt. %, in relation to the total weight ofthe matrix layer.

Especially, the oral thin film according to the invention is preferablyalso characterised in that the at least one pharmaceutically activeagent, preferably ketamine, is present in the matrix layer in an amountof 60 wt. %, in relation to the total weight of the matrix layer.

The oral thin film according to the invention is preferably alsocharacterised in that the at least one pharmaceutically active agent,preferably ketamine, is present in the form of microcrystals.

Suitable mean crystal sizes of these microcrystals lie preferably in therange of 1 to 1000 μm or in the range of 5 to 500 μm or in the range of10 to 200 μm. The mean crystal size especially preferably lies in therange of 15 to 25 μm, especially in the range of 20 to 22 μm. Thecrystal size can be determined, for example, by means of lightmicroscopy or by means of micro computer tomography X-ray (micro-CT).

Unless stated otherwise, all cited molecular weights of polymers relateto the weight-average molecular weight (Mw), determined by means of gelpermeation chromatography.

The oral thin film according to the invention is also preferablycharacterised in that the at least one polyvinyl alcohol comprises apolyvinyl alcohol with a mean molecular weight of approximately 25,000to approximately 250,000 g/mol.

The oral thin film according to the invention is also preferablycharacterised in that the at least one polyvinyl alcohol comprises apolyvinyl alcohol with a mean molecular weight of approximately 25,000to approximately 35,000 g/mol and/or a polyvinyl alcohol with a meanmolecular weight of approximately 200,000 to 210,000 g/mol.

According to the present invention, polyvinyl alcohols with a meanmolecular weight of approximately 31,000 (4-88) to approximately 205,000(40-88) g/mol are especially suitable.

According to the present invention, polyvinyl alcohols with a meanmolecular weight with approximately 31,000 (4-88) to approximately205,000 (40-88) g/mol are especially suitable.

According to the present invention, polyvinyl alcohols with a viscosityof 3.4 to 4.6 mPas (4-88) to 34 to 46 mPas (40-88) mPas in a 40 g/laqueous solution, determined by the “falling ball method” (Ph.Eur.2.2.49), are also especially suitable, or mixtures of two or moredifferent ones of these PVA types.

According to the present invention, polyvinyl alcohols with a viscosityof 3.4 to 4.6 mPas (4-88) or of 34 to 46 mPas (40-88) mPas in a 40 g/laqueous solution, determined by the “falling ball method” (Ph.Eur.2.2.49), are also especially suitable, or mixtures of two or moredifferent ones of these PVA types.

The oral thin film according to the invention is also preferablycharacterised in that the at least one polyvinyl alcohol-polyethyleneglycol graft copolymer has a polyethylene glycol main chain onto whichthere are grafted polyvinyl alcohol units.

The oral thin film according to the invention is also preferablycharacterised in that the at least one polyvinyl alcohol-polyethyleneglycol graft copolymer has a polyethylene glycol main chain onto whichthere are grafted polyvinyl alcohol units, wherein the molar ratio ofpolyethylene glycol to polyvinyl alcohol is 1:3.

The oral thin film according to the invention is also preferablycharacterised in that the at least one polyvinyl alcohol-polyethyleneglycol graft copolymer has a polyethylene glycol main chain onto whichthere are grafted polyvinyl alcohol units, wherein the polyvinylalcohol-polyethylene glycol graft copolymer has a mean molecular weightin the range of 40,000 to 50,000 g/mol, preferably of approximately45,000 g/mol.

A suitable and preferred polyvinyl alcohol-polyethylene glycol graftcopolymer is known by the trade name Kollicoat IR (BASF).

The oral thin film according to the invention is also preferablycharacterised in that the at least one polyvinyl alcohol is provided inthe matrix layer in an amount of 5 to 40 wt. %, preferably of 5 to 20wt. %, of 5 to 19 wt. %, of 5 to 18 wt. %, of 5 to 17 wt. %, of 5 to 16wt. %, of 5 to 15 wt. %, of 5 to 14 wt. %, of 5 to 13 wt. %, of 5 to 12wt. %, of 5 to 11 wt. % or of 5 to 10 wt. %, in relation to the totalweight of the matrix layer.

The oral thin film according to the invention is also preferablycharacterised in that the at least one polyvinyl alcohol-polyethyleneglycol graft copolymer is provided in the matrix layer in an amount of15 to 45 wt. %, preferably of 17 to 40 wt. %, or 20 to 30 wt. %, inrelation to the total weight of the matrix layer.

In another embodiment, the oral thin film according to the invention isalso preferably characterised in that the at least one polyvinylalcohol-polyethylene glycol graft copolymer is provided in the matrixlayer in an amount of 10 to 30 wt. %, preferably of 15 to 25 wt. %, of17.5 to 22.5 wt. % or of 19 to 21 wt. %, especially of approximately19.5 to 20.5 wt. %, and especially preferably of approximately 20 wt. %or of 20.1 wt. %, in relation to the total weight of the matrix layer.

The oral thin film according to the invention is also preferablycharacterised in that the matrix layer also comprises at least oneauxiliary substance selected from the group comprising colouring agents,flavourings, sweeteners, softeners, taste-masking agents, emulsifiers,enhancers, pH regulators, humectants, preservatives and/or antioxidants.

Each of these auxiliary substances is preferably contained in each casein an amount of 0.1 to 15 wt. %, preferably of 0.1 to 10 wt. %, or of0.1 to 5 wt. %, in relation to the total weight of the matrix layer.

Sweeteners, such as saccharin Na and/or sucralose are preferablycontained in the matrix layer in a total amount of 2 to 5 wt. %,especially approximately 3 wt. %, in relation to the total weight of thematrix layer.

Apart from sweeteners, flavourings are preferably contained in thematrix layer in a total amount of 2 to 5 wt. %, especially approximately3 wt. %, in relation to the total weight of the matrix layer.

Colouring agents are preferably contained in the matrix layer in a totalamount of 0.1 to 1 wt. %, especially approximately 0.4 wt. %, inrelation to the total weight of the matrix layer.

The oral thin film according to the invention is not subjected to anylimitations in respect of its structure.

The oral thin film according to the invention can thus be provided inthe form of a single-layer oral thin film and thus can consist merely ofthe matrix layer as defined above.

In another embodiment, the oral thin film according to the invention canthus be provided in the form of a multi-layer oral thin film and thuscan contain further layers in addition to the matrix layer as definedabove.

This plurality of layers can be laminated directly on top of one anotheror can be connected to an adhesive layer arranged in between.

An adhesive layer is understood to mean a layer that can act as anadhesive, as defined in DIN EN 923:2016-03. A non-adhesive layertherefore cannot act as an adhesive as defined above.

Especially, water-soluble adhesive layers as described in DE 10 2014 127452 A1 are suitable as adhesive layers, and the content of that documentin this regard is hereby expressly incorporated fully in the presentdisclosure.

For example, buffer layers for setting a pH value or slowly dissolvingor insoluble layers which protect the oral thin film against prematureerosion can be provided as further layers.

Alternatively, further matrix layers can be provided, which containother pharmaceutically active agents or flavourings or taste-maskingagents.

In one embodiment the oral thin film according to the invention ischaracterised in that the matrix layer is in the form of a smooth film.This means that the matrix layer, for example, is not provided in theform of a foam.

A smooth film is preferably characterised in that a smooth film has avolume fraction of 0 to 5%, in relation to the total volume of thematrix layer, of bubbles or cavities. The cavities are filled herepreferably with air or a gas, preferably with an inert gas, especiallypreferably with nitrogen, carbon dioxide, helium or a mixture of atleast two of these gases. The diameter of the bubbles or cavitiesgenerally lies in the range of 0.01 to 350 μm. The diameter of thebubbles or cavities especially preferably lies in the range of 10 and200 μm.

In another embodiment the oral thin film according to the invention ischaracterised in that the matrix layer is in the form of a solidifiedfilm having cavities.

Especially, the infiltration of water or saliva or other bodily fluidsinto the interior of the dosage form is facilitates by the cavities andthe associated larger surface of the films, and therefore the dissolvingof the dosage form and the active agent release are accelerated.

In the case of a quickly resorbing active agent, the transmucosalresorption can be improved additionally by the quick dissolution of thematrix layer.

On the other hand, the wall thickness of said cavities is preferablylow, since these represent, for example, solidified bubbles, and sothese cavities dissolve or break down quickly.

A further advantage of this embodiment lies in the fact that, due to theformulation as a foam, a quicker drying can be provided than for acomparable, non-foamed composition, in spite of the comparatively higharea density.

The multi-layer oral thin film according to the invention is preferablycharacterised in that the cavities are isolated from one another and arepreferably provided in the form of bubbles, wherein the cavities arefilled with air or a gas, preferably with an inert gas, especiallypreferably with nitrogen, carbon dioxide, helium or a mixture of atleast two of these gases.

According to another embodiment it is provided that the cavities areconnected to one another preferably by forming a cohesive channel systempenetrating the matrix.

Said cavities preferably have a volume fraction of 5 to 98%, preferablyof 50 to 80%, in relation to the total volume of the matrix layer. Inthis way, the advantageous effect of accelerating the dissolving of thematrix layer is favourably influenced.

Furthermore, surface-active substances or surfactants can be added tothe matrix layer for foam formation or to the obtained foam before orafter the drying in order to improve the stability of the foam before orafter the drying.

A further parameter that influences the properties of the dosage formaccording to the invention is the diameter of the cavities or bubbles.The bubbles or cavities are preferably produced with the aid of afoaming machine, with which the diameter of the bubbles can be setwithin a wide range, almost arbitrarily. The diameter of the bubbles orcavities can thus lie in the range of 0.01 to 350 μm. The diameterespecially preferably lies in the range of 10 and 200 μm.

The oral thin film according to the invention preferably has an area of0.5 cm² to 10 cm², especially preferably of 2 cm² to 8 cm² or of 4 cm²to 5 cm².

The area density of the matrix layer or of a further layer possiblyprovided is, in each case, preferably at least 10 g/m², more preferablyat least 20 g/m² or at least 30 g/m² or most preferably 50 g/m², or lessthan or equal to 400 g/m², more preferably less than or equal to 350g/m², or less than or equal to 300 g/m² or most preferably less than 250g/m². The area density is preferably 10 to 400 g/m², more preferably 20to 350 g/m², or 30 to 300 g/m² and most preferably 50 to 250 g/m².

Each of the provided layers, especially the matrix layer, preferably hasin each case a layer thickness of preferably 10 μm to 500 μm, especiallypreferably of 20 μm to 300 μm.

If the various layers, especially the matrix layer, are present in theform of a solidified foam, it is thus preferred that each of the layersprovided as a foam has, in each case, a layer thickness of preferably 10μm to 3000 μm, especially preferably of 90 μm to 2000 μm.

The oral thin film according to the invention is also preferablycharacterised in that the at least one pharmaceutically active agent ispresent in the matrix layer in a total amount of 25 mg to 150 mg,preferably of 25 mg to 125 mg, especially of approximately 50 mg to 150mg.

The oral thin film according to the invention is especiallycharacterised in that the at least one pharmaceutically active agent ispresent in the matrix layer in a total amount of 50 mg to 100 mg,preferably of approximately 50 mg or approximately 100 mg.

The oral thin film according to the invention is also preferablycharacterised in that the at least one pharmaceutically active agentcomprises ketamine, preferably in the form of a free base or ketamineHCl, in a total amount of 25 mg to 150 mg, preferably of 25 mg to 125mg, especially of approximately 50 mg to 150 mg.

The oral thin film according to the invention is especiallycharacterised in that the at least one pharmaceutically active agentketamine, preferably in the form of a free base or ketamine HCl, ispresent in the matrix layer in a total amount of 50 mg to 100 mg,preferably of approximately 50 mg or approximately 100 mg.

The oral thin film according to the invention is also preferablycharacterised in that the at least one pharmaceutically active agent ispresent as ketamine, preferably in the form of a free base or ketamineHCl, is present in the matrix layer in a total amount of 25 mg to 150mg, preferably of 25 mg to 125 mg, especially of approximately 50 mg to150 mg.

The oral thin film according to the invention is especiallycharacterised in that the at least one pharmaceutically active agent asketamine, preferably in the form of a free base or ketamine HCl, ispresent in the matrix layer in a total amount of 50 mg to 100 mg,preferably of approximately 50 mg or approximately 100 mg.

The oral thin film according to the invention is also preferablycharacterised in that the at least one pharmaceutically active agent asketamine, preferably in the form of a free base or ketamine HCl, ispresent in the matrix layer in a total amount of 2 mg or 5 mg or 7 mg or10 mg or 15 mg or 20 mg or 25 mg or 30 mg or 35 mg or 40 mg or 45 mg or50 mg or 55 mg or 60 mg or 65 mg or 70 mg or 80 mg or 90 mg or 95 mg or100 mg or 105 mg or 110 mg or 115 mg or 120 mg or 125 mg or 130 mg or135 mg or 140 mg or 145 mg or 150 mg.

The oral thin film according to the invention is also preferablycharacterised in that the puncture strength is at least 0.15 N/mm²,preferably at least 0.18 N/mm², especially preferably 0.20 N/mm² ormore. The area density here is preferably 150 to 250 g/m², especiallypreferably 180 to 220 g/m².

The puncture strength is preferably determined as follows:

Used test device: Sauter FH-20 force gauge.

Test area: round test area of diameter 5 mm.

Execution:

The force gauge is fixed and a 10 cm² laminate specimen is placedcentrally on the test area of the device (round test area of diameter 5mm). The laminate specimen is fixed at the edges and a force is exertedin the direction of the test specimen, which force is increased untilthe laminate specimen is punctured. The resultant maximum value of theforce that was applied to the specimen until puncture is measured. Themeasurement is performed with n=3 laminate specimens per laminate batch.

The oral thin film according to the invention is also preferablycharacterised in that the bioavailability of the at least onepharmaceutically active agent, especially the ketamine, preferably inthe form of a free base or ketamine HCl, is at least 5% or at least 10%or at least 15% or at least 20% or at least 25% or at least 30% or atleast 35% or at least 40% or at least 45% or at least 50% or at least55% or at least 60% or at least 65% or at least 70% or at least 75% orat least 80% or at least 85% or at least 90% or at least 95% or at least97% or at least 99%

The oral thin film according to the invention is also preferablycharacterised by the following release rates, wherein the release raterelates to the release of the at least one pharmaceutically activeagent, preferably the ketamine, after a certain time followingapplication of the oral thin film according to the invention.

It is preferred if, after 1 min, at least 40% or at least 50% of the atleast one pharmaceutically active agent, preferably the ketamine, arereleased.

It is preferred if, after 2 min, at least 75% or at least 80% or atleast 85% of the at least one pharmaceutically active agent, preferablythe ketamine, are released.

It is preferred if, after 15 s, approximately 5 to 10% of the at leastone pharmaceutically active agent, preferably the ketamine, arereleased.

It is preferred if, after 30 s, approximately 20 to 25% of the at leastone pharmaceutically active agent, preferably the ketamine, arereleased.

It is preferred if, after 45 s, approximately 30 to 40% of the at leastone pharmaceutically active agent, preferably the ketamine, arereleased.

It is preferred if, after 1 min, approximately 50 to 60% of the at leastone pharmaceutically active agent, preferably the ketamine, arereleased.

It is preferred if, after 1 min and 15 s, approximately 60 to 70% of theat least one pharmaceutically active agent, preferably the ketamine, arereleased.

It is preferred if, after 1 min and 30 s, approximately 70 to 80% of theat least one pharmaceutically active agent, preferably the ketamine, arereleased.

It is preferred if, after 1 min and 45 s, approximately 80 to 85% of theat least one pharmaceutically active agent, preferably the ketamine, arereleased.

It is preferred if, after 2 min, approximately 82 to 88% of the at leastone pharmaceutically active agent, preferably the ketamine, arereleased.

It is preferred if, after 2 min and 15 s, approximately 84 to 90% of theat least one pharmaceutically active agent, preferably the ketamine, arereleased.

It is preferred if, after 2 min and 30 s, approximately 86 to 92% of theat least one pharmaceutically active agent, preferably the ketamine, arereleased.

Hereinafter, preferred embodiments in respect of the maximum plasmaconcentration (Cmax) of the active agent or metabolites thereof will bedescribed for the oral thin film according to the invention, in which(S)-ketamine is used as pharmaceutically active agent.

100 mg (S)-ketamine can be administered here in one dose or by means oftwo doses of 50 mg each of (S)-ketamine.

The oral thin film according to the invention is preferablycharacterised in that the maximum plasma concentration of (S)-ketaminefollowing administration of a dose of 50 mg of (S)-ketamine lies at 50to 200 ng/mL.

The oral thin film according to the invention is also preferablycharacterised in that the maximum plasma concentration of the ketaminemetabolite (S)-norketamine following administration of a dose of 50 mgof (S)-ketamine lies at 200 to 400 ng/mL.

The oral thin film according to the invention is also preferablycharacterised in that the maximum plasma concentration of the ketaminemetabolite (S)-hydroxynorketamine following administration of a dose of50 mg of (S)-ketamine lies at 50 to 150 ng/mL.

The oral thin film according to the invention is preferablycharacterised in that the maximum plasma concentration of (S)-ketaminefollowing administration of a dose of 100 mg of (S)-ketamine lies at 100to 200 ng/mL.

The oral thin film according to the invention is also preferablycharacterised in that the maximum plasma concentration of the ketaminemetabolite (S)-norketamine following administration of a dose of 100 mgof (S)-ketamine lies at 300 to 500 ng/mL.

The oral thin film according to the invention is also preferablycharacterised in that the maximum plasma concentration of the ketaminemetabolite (S)-hydroxynorketamine following administration of a dose of100 mg of (S)-ketamine lies at 100 to 250 ng/mL.

The oral thin film according to the invention is preferablycharacterised in that the maximum plasma concentration of (S)-ketaminefollowing administration of a dose of 50 mg of (S)-ketamine lies at 70to 120 ng/mL.

The oral thin film according to the invention is also preferablycharacterised in that the maximum plasma concentration of the ketaminemetabolite (S)-norketamine following administration of a dose of 50 mgof (S)-ketamine lies at 200 to 300 ng/mL.

The oral thin film according to the invention is also preferablycharacterised in that the maximum plasma concentration of the ketaminemetabolite (S)-hydroxynorketamine following administration of a dose of50 mg of (S)-ketamine lies at 70 to 120 ng/mL.

The oral thin film according to the invention is preferablycharacterised in that the maximum plasma concentration of (S)-ketaminefollowing administration of a dose of 100 mg of (S)-ketamine lies at 120to 160 ng/mL.

The oral thin film according to the invention is preferablycharacterised in that the maximum plasma concentration of the ketaminemetabolite (S)-norketamine following administration of a dose of 100 mgof (S)-ketamine lies at 300 to 350 ng/mL.

The oral thin film according to the invention is preferablycharacterised in that the maximum plasma concentration of the ketaminemetabolite (S)-hydroxynorketamine following administration of a dose of100 mg of (S)-ketamine lies at 150 to 220 ng/mL.

The oral thin film according to the invention is preferablycharacterised in that the maximum plasma concentration of (S)-ketaminefollowing sublingual administration of a dose of 50 mg of (S)-ketaminelies at 70 to 120 ng/mL.

The oral thin film according to the invention is preferablycharacterised in that the maximum plasma concentration of the ketaminemetabolite (S)-norketamine following sublingual administration of a doseof 50 mg of (S)-ketamine lies at 200 to 300 ng/mL.

The oral thin film according to the invention is preferablycharacterised in that the maximum plasma concentration of the ketaminemetabolite (S)-hydroxynorketamine following administration of a dose of50 mg of (S)-ketamine lies at 70 to 120 ng/mL.

The oral thin film according to the invention is preferablycharacterised in that the maximum plasma concentration of (S)-ketaminefollowing sublingual administration of a dose of 100 mg of (S)-ketaminelies at 120 to 160 ng/mL.

The oral thin film according to the invention is preferablycharacterised in that the maximum plasma concentration of the ketaminemetabolite (S)-norketamine following sublingual administration of a doseof 100 mg of (S) ketamine lies at 300 to 350 ng/mL.

The oral thin film according to the invention is preferablycharacterised in that the maximum plasma concentration of the ketaminemetabolite (S)-hydroxynorketamine following sublingual administration ofa dose of 100 mg of (S)-ketamine lies at 150 to 220 ng/mL.

The oral thin film according to the invention is preferablycharacterised in that the maximum plasma concentration of (S)-ketaminefollowing buccal administration of a dose of 50 mg of (S)-ketamine liesat 80 to 160 ng/mL.

The oral thin film according to the invention is preferablycharacterised in that the maximum plasma concentration of the ketaminemetabolite (S)-norketamine following buccal administration of a dose of50 mg of (S)-ketamine lies at 200 to 280 ng/mL.

The oral thin film according to the invention is preferablycharacterised in that the maximum plasma concentration of the ketaminemetabolite (S)-hydroxynorketamine following buccal administration of adose of 50 mg of (S)-ketamine lies at 60 to 100 ng/mL.

The oral thin film according to the invention is preferablycharacterised in that the maximum plasma concentration of (S)-ketaminefollowing buccal administration of a dose of 100 mg of (S)-ketamine liesat 120 to 200 ng/mL.

The oral thin film according to the invention is preferablycharacterised in that the maximum plasma concentration of the ketaminemetabolite (S)-norketamine following buccal administration of a dose of100 mg of (S)-ketamine lies at 400 to 500 ng/mL.

The oral thin film according to the invention is preferablycharacterised in that the maximum plasma concentration of the ketaminemetabolite (S)-hydroxynorketamine following buccal administration of adose of 50 mg of (S)-ketamine lies at 120 to 200 ng/mL.

The oral thin film according to the invention is also preferablycharacterised in that the matrix layer comprises 60 wt. % of(S)-ketamine HCl, 10 wt. % of the polyvinyl alcohol 40-88 as definedpreviously, and 20 wt. % or 20.1 wt. % of a polyvinylalcohol-polyethylene glycol graft copolymer as defined previously.

The oral thin film according to the invention is also preferablycharacterised in that the matrix layer comprises 60 wt. % of(S)-ketamine HCl, 10 wt. % of the polyvinyl alcohol 40-88 as definedpreviously, and 20.1 wt. % of a polyvinyl alcohol-polyethylene glycolgraft copolymer, preferably as defined previously, 1.0 wt. % ofsaccharin Na, 2.0 wt. % of sucralose, 3.5 wt. % of glycerol, 3.0 wt. %of a pharmaceutically acceptable flavouring and 0.4 wt. % of apharmaceutically acceptable colouring agent. Pure water is preferablyused here as solvent.

In a very especially preferred embodiment the oral thin film has aformulation according to formulation 15 in Table 3.

The oral thin film according to the invention can be produced byconventional methods.

The above definitions in relation to the oral thin film apply similarlyfor the method according to the invention.

A method for producing the oral thin film according to the inventionpreferably comprises the steps of:

a) producing a solution, dispersion or melt comprising the at least onepharmaceutically active agent, the at least one polyvinyl alcohol andthe at least one polyvinyl alcohol-polyethylene glycol graft copolymer;

a1) optionally foaming the solution, dispersion or melt from step a) byintroducing a gas or gas mixture, by chemical gas generation or byexpansion of a dissolved gas,

b) the solution, dispersion or melt from step a) or the optionallyfoamed solution, dispersion or melt from step at.

It is clear to a person skilled in the art that step at) is necessaryonly if the matrix layer is to be provided in the form of a solidifiedfoam having cavities.

The bubbles or cavities are preferably produced with the aid of afoaming machine, with which the diameter of the bubbles can be setwithin a wide range, almost arbitrarily.

The present invention also relates to an oral thin film obtainable bythe method described above.

In addition, the present invention relates to an oral thin film, asdescribed above or obtainable by the above-described method, as amedicament.

In addition, the present invention relates to an oral thin film, asdescribed above or obtainable by the above-described method, as amedicament for sublingual and/or buccal administration.

In addition, the present invention relates to an oral thin film, asdescribed above or obtainable by the above-described method, as amedicament for use in the treatment of pain and/or depression.

In addition, the present invention relates to an oral thin film, asdescribed above or obtainable by the above-described method, as amedicament for use in the treatment of pain and/or depression bysublingual and/or buccal administration of the oral thin film.

The present invention additionally relates to an oral thin film, asdescribed above or obtainable by the above-described method, whereinketamine, preferably (S)-ketamine, or a pharmaceutically acceptable saltthereof, is used as pharmaceutically active agent in the matrix layer,for use in the treatment of pain and/or depression, especially to reducethe risk of suicide and/or for use as a general anaesthetic, preferablyto initiate and carry out general anaesthesia, or as a supplement in thecase of local anaesthesia and/or as an analgesic.

The present invention relates especially to an oral thin film asdescribed above or obtainable by the above-described method, whereinketamine, preferably (S)-ketamine, or a pharmaceutically acceptable saltthereof is used as pharmaceutically active agent in the matrix layer,for use in the treatment of pain, preferably as defined hereinafter.

The term “pain” is generally understood to mean a feeling of pain thatis often caused by intense or noxious stimuli. Pain that is chronic orongoing is understood to be long-lasting, and pain that disappearsquickly is said to be acute.

Nociceptive pain is pain caused by the stimulation of sensory nervefibres which respond to stimuli approaching or surpassing a noxiousintensity (nociceptors) and can be classified according to the mode ofthe noxious stimulation. The most common categories are thermal,mechanical and chemical stimulation. Some nociceptors respond to morethan one modality and are therefore termed as being polymodal.

Nociceptive pain can also be subdivided into “visceral”, “deep somatic”and “superficial somatic” pain.

Neuropathic pain is generally caused by an injury or illness affecting apart of the nervous system involved in body sensation (the somatosensorysystem).

Neuropathic pain can be subdivided into peripheral, central or mixed(peripheral and central) neuropathic pain. Peripheral neuropathic painis often described as “burning”, “tingling”, “electric” or “piercing”.

The present invention also relates to a method for treating pain and/ordepression in a patient, comprising the application of an oral thinfilm, as described above, to a mucous membrane of the patient.

The method for treating pain and/or depression in a patient ispreferably characterised in that the mucous membrane comprises the oralmucosa.

The method for treating pain and/or depression in a patient ispreferably characterised in that the oral thin film according to theinvention is applied sublingually or buccally.

The method for treating pain and/or depression in a patient ispreferably characterised in that the dosing of the at least onepharmaceutically active agent, preferably ketamine, especially in theform of a free base or ketamine HCl, is approximately 50 mg to 150 mg,preferably approximately 50 mg or approximately 100 mg.

The method for treating pain and/or depression in a patient ispreferably characterised in that the oral thin film preferably isapplied for a period of less than 2 min, especially of 30 s to 90 s,preferably of 30 s to 60 s and preferably dissolves during this time.

The invention will be described in greater detail hereinafter on thebasis of non-limiting examples.

EXAMPLES Example 1

The starting materials stated in Table 1 were used in the followingexamples.

TABLE 1 Starting material Function (S)-ketamine HCl API Polyvinylalcohol Matrix polymer (PVA) 4-88 (35% solution) Polyvinyl alcoholMatrix polymer (PVA) 40-88 (15%solution) Kollicoat IR Matrix polymer(30% solution) Glycerol Plasticiser Sucralose Sweetener Saccharin NaSweetener Cherry Flavour Flavouring M55394 (EU taste) FD&C Red 40Colouring agent Purified water Process solvent P 120 g/m², PE2 Coatingliner AB1

A plurality of oral thin films were produced from these startingmaterials by the method according to the invention and were examined.The composition of these is stated in Table 2.

TABLE 2 1 2 3 4 5 6 7 8 9 10 Material [wt. %] [wt. %] [wt. %] [wt. %][wt. %] [wt. %] [wt. %] [wt. %] [wt. %] [wt. %] (S)-ketamine HCl 55.0 50.0  50.0  60.0  60.0  55.0  60.0  65.0  60.0  60.0  PVA 4-88 35.0  — —30.5  — — — — — — PVA 40-88 — — 9.9 — 7.6 8.8 9.9 6.4 — 2.0 Kollicoat IR— 39.5  29.6  — 22.9  26.2  20.6  19.1  30.5  28.5  Saccharin Na 1.0 1.01.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 Sucralose 2.0 2.0 2.0 2.0 2.0 2.0 2.02.0 2.0 2.0 Glycerol 4.0 4.0 4.5 3.5 3.5 4.0 3.5 3.5 3.5 3.5 CherryFlavour 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 M55394 Solvent Aq. Pur.Aq. Pur. Aq. Pur. Aq. Pur. Aq. Pur. Aq. Pur. Aq. Pur. Aq. Pur. Aq. Pur.Aq. Pur. Foam/Film Foam Film Foam Foam Foam Foam Foam Foam Film Foam

All oral thin films according to the invention with the compositionsstipulated in Table 2 solve the problem addressed by the invention.

Based on composition 2, further oral thin films were produced having thecomposition according to Table 3 and were tested.

TABLE 3 11 12 13 14 15 Material [wt. %] [wt. %] [wt. %] [wt. %] [wt. %](S)-ketamine 60.0 55.0 60.0 60.0 60.0 HCl PVA 4-88 — — 5.0 10.0 — PVA40-88 5.0 5.0 — — 10.0 Kollicoat IR 25.1 30.1 25.1 20.1 20.1 SaccharinNa 1.0 1.0 1.0 1.0 1.0 Sucralose 2.0 2.0 2.0 2.0 2.0 Glycerol 3.5 3.53.5 3.5 3.5 Cherry Flavour 3.0 3.0 3.0 3.0 3.0 M55394 FD&C Red 0.4 0.40.4 0.4 0.4 No, 40 Solvent Aq. Pur. Aq. Pur. Aq. Pur. Aq. Pur. Aq. Pur.Test Good Good Good Good Very film, film, film, film, good small bubblesbubbles small film, few particles visible, visible, particles bubbles,visible rough rough visible very good surface surface tear strength

All oral thin films with the compositions stipulated in Table 3 solvethe problem addressed by the invention.

Formulation 15 was examined in detail.

Formulation 15 is stable for 9 months at 25° C./60 r.h. %-40°/r.h. 75%.

The residual water content of formulation 15 was determined by means ofKarl Fischer titration.

The residual water content of 6 samples was determined. The determinedresidual water content was 4.40 wt. %, 3.82 wt. %, 4.02 wt. %, 4.51 wt.%, 4.91 wt. % and 4.57 wt. %.

This residual water content is acceptable.

The disintegration time of formulation 15 in a 1 L glass beaker with 900ml dimineralised water (temperature-controlled to 37° C.±2° C.) wasdetermined.

The disintegration time of six samples was determined. The determineddisintegration time was 52 s, 55 s, 58 s, 56 s, 54 s and 55 s.

Formulation 15 thus has a good disintegration time.

The in vitro release of the active agent was also determined fromformulation 15.

With the in vitro release, (S)-ketamine is released from (S)-ketamineHCl-containing oral thin films and is determined. The active agent isreleased in phosphate buffer pH 6.8 USP and is then determined by insitu fibre optic UV system. The quantification was performed against anexternal standard.

The release is performed with Dissolution Apparatus 2—(Paddle oversinker) according to USP <711>,

TABLE 4 Stainless Steel Capsule Sinker with 10 Spirals, 31.0 × 11.0 mmCapacity Sinker: (Sotax Style) Stirring speed: 50 rpm Distance betweenthe vessel base and 25 mm ± 2 mm the lower edge of the paddle:Temperature: 37° C. ± 0.5° C. Release medium: Phosphate buffer pH 6.8USP Release medium volume: 500 mL Sample measurement intervals: Every 5seconds (0 to 5 min) Every 10 seconds (5 to 10 min) Every 15 seconds (10to 15 min)

The results of the release study are shown and FIG. 1 and were asfollows:

after 15s approx. 11% after 30s approx. 24% after 45s approx. 38% after1 minute approx. 54% after 1 minute 15s approx. 68% after 1 minute 30sapprox. 78% after 1 minute 45s approx. 83% after 2 minutes approx. 85%after 2 minutes 15s approx. 86% after 2 minutes 30s approx. 87%

Example 2

The formulations from Table 3 were examined in greater detail in furtherstudies.

1. Measurement of the Puncture Strength

Execution of the measurement (test of the puncture strength of thelaminate):

Used test device: Sauter FH-20 force gauge.

Test area: round test area of diameter 5 mm.

The commercially obtainable product: “LISTERINE POCKETPAKS® COOL MINTORAL CARE FRESH BREATH STRIPS” was used as comparison product. Thiscontains pullulan, menthol, Acesulfame potassium, copper gluconate,polysorbate 80, chondrus crispus gum (Carrageenan), glyceryl oleate,thymol, eucalyptol, methyl salicylate, Ceratonia siliqua gum (locustbean gum), propylene glycol, xanthan gum, aroma (flavouring), FD&C BlueNo. 1 (colouring agent) and FD&C Green No. 3 (colouring agent).

Execution:

The force gauge was fixed and a 10 cm² laminate specimen (for Listerine,a 32 mm×22 mm Listerine OTF was used) was placed centrally on the testarea of the device (round test area of diameter 5 mm). The laminatespecimen was fixed at the edges and a force was exerted in the directionof the test specimen; the force was increased until the laminatespecimen was punctured. The resultant maximum value of the force thatwas applied to the test specimen until puncture was measured. Themeasurement was performed with n=3 laminate specimens per laminate batch(for Listerine, n=3 measurement with OTF).

The results are summarised in the following Table 5:

TABLE 5 Standard Puncture Average deviation Area density strengthFormulation [N] [N] [g/m²] [N/mm²] 2 1.96 0.09 150 0.10 3 2.22 0.10 1300.11 5 1.85 0.06 157 0.09 5 2.88 0.19 206 0.15 7 2.92 0.08 167 0.15 81.27 0.12 145 0.06 9 1.55 0.12 190 0.08 10 1.79 0.15 156 0.09 11 2.680.20 188 0.14 12 2.63 0.05 172 0.13 13 2.04 0.05 184 0.10 14 2.26 0.11180 0.12 15 4.00 0.15 206 0.20 Listerine 3.14 0.80 46.3 0.16(comparison)

All shown examples have a good puncture strength (comparable to theproduct Listerine as reference) in spite of high active agent load.

Example 3

As stated in the description, the oral thin film according to theinvention is preferably characterised in that the at least onepharmaceutically active agent, preferably ketamine, is present in theform of microcrystals. Suitable mean crystal sizes of thesemicrocrystals lie preferably in the range of 1 to 1000 μm or in therange of 5 to 500 μm or in the range of 10 to 200 μm. The crystal sizecan be determined, for example, by means of light microscopy or by meansof micro computer tomography X-ray (micro-CT).

Micro computer tomography (micro CT) x-ray test method and measurementconditions:

Instrument SkyScan 2211

X-ray energy 60 kV

Resolution 0.75 μm/voxel

Reconstruction according to Feldkamp

The results are summarised in the following Table 6:

TABLE 6 Crystal size and Formulation standard deviation  4 20.1 μm +-7.2 μm  7 18.4 μm +- 6.8 μm 14 16.9 μm +- 6.2 μm 15 21.0 μm +- 7.8 μm

Example 4

Results of a clinical study with an OTF based on formulation 15according to Table 3.

Aim:

Primary objective: Determination of the pharmacokinetic profile of anoral thin film of (S)-ketamine with 50 mg (S)-ketamine; Secondaryobjective: (1) Determination of the pharmacodynamic profile of an oralthin film of (S)-ketamine with 50 or 100 mg (S)-ketamine with the endpoints antinociceptors and psychomimetic side effects; (2) Determinationof the safety and compatibility of the (S)-ketamine oral thin film.

Study Design:

The study had an explorative, open, crossover and randomised design. Alltest subjects were treated twice. The test subjects received 50 mg(S)-ketamine OTF once and two 50 mg (S)-ketamine OTF once (total dosethus 100 mg) in a random order. 15 test subjects received the OTFsublingually; 5 further test subjects received the OTF buccally.

Execution of the Study:

During one test run, the test subjects received an individual 50 mg(S)-ketamine OTF either sublingually (n=15) or buccally (n=5) During afurther test run, the test subjects received simultaneously two 50 mg(S)-ketamine OTFs sublingually (n=15) or buccally (n=5) Six hours afterthe OTF administration, a low (S)-ketamine dose (20 mg) was administeredto the test subjects intravenously. A wash-out phase of at least 2 dayswas provided between the study days.

Blood Sampling:

For blood sampling, an arterial access was placed in the left or rightradial or brachial artery. Blood samples (4 ml) were taken at thefollowing intervals following OTF administration (t=0 min): 0, 5, 10,20, 40, 60, 90, 120, 180, 240, 300, 360 min and at the followingintervals following the start of intravenous administration: 2, 4, 10,15, 20, 30, 40, 60, 75, 90 and 120 min.

Pain Tests:

Three pain tests were performed at intervals of 10 to 20 minutes (atintervals of 10 to 60 minutes(0-10-20-30-40-60-80-100-120-150-180-240-300-360 minutes)

a) pressure pain,

b) electrical pain and

c) heat-induced pain.

a) The test subjects assessed their pressure pain threshold in responseto an increasing pressure stimulus using an FDN 200 Algometer fromWagner Instruments.

b) The test subject used a transcutaneous electrical pain model toassess the pain threshold during a fixed stimulation of the skin so thatthe pain value was 7 to 8.

c) A fixed heat stimulus that caused a pain value of 7 to 8 was appliedto the skin using the Medoc Pathway System.

All pain assessments were performed using an 11-stage Likert scale(Verbal Rating Scale, VRS), which ranged from 0 (no pain) to 10 (maximumpain imaginable).

Qualitative Results:

The taste of the film formulations was described by the test subjects asbeing acceptable. No safety-relevant results were reported. Neither thesublingual nor the buccal administration were considered to beproblematic.

Plasma Concentrations:

The plasma concentration was measured by means of liquid chromatographycoupled with QTOF-MS as detection method. The lower detection limit was6 ng/mL, 6 ng/mL and 4 ng/mL for (S)-ketamine, (S)-norketamine and(S)-hydroxynorketamine respectively. The upper detection limit was 1000,500 and 200 ng/mL for (S)-ketamine, (S)-norketamine and(S)-hydroxynorketamine respectively.

Questionnaires:

Immediately before the pain test, two questionnaires were filled outwith an interval of 30 minutes in between in order to assess the effectof the medicinal treatment for psychological and psychomimetic sideeffects (0-30-60-90—etc. from 0 to 360 minutes).

1. Bowdle questionnaire: Based on the Bowdle questionnaire (Bowdle et al“Psychedelic effects of ketamine in healthy volunteers: relationship tosteady-state plasma concentrations” Anesthesiology 1998 January; 88(1):82-8) it is possible to deduce three factors of psychedelic effects:drug intoxication, internal perception and external perception.

2. Bond and Lader questionnaire: The Bond and Lader scales arecalculated from sixteen 100 mm visual analogue scales. The end pointsare set to antonymous word pairs, such as ‘awake-sleepy’, ‘wellcoordinated-clumsy’, ‘mentally slow-quickly attentive’ and‘incompetent-professional’.

Results:

The results show the rapid onset of a powerful and long-lastingreduction in pain (see FIG. 2). No dose dependency for the pain reliefwas observed for the OTF formulation. This is presumably due to the highconcentration of the metabolite norketamine, which brings about ananti-analgesic effect (see Olofsen et al “Estimation of contribution ofnorketamine to ketamine-induced acute pain relief and neurocognitiveimpairment in healthy volunteers” Anesthesiology 2012; 117; Addendum 5).

A non-linear dose-dependent increase in the concentration of ketamineand the metabolites norketamine and hydroxynorketamine was observed forthe OTF formulation.

The plasma level of the metabolites (S)-norketamine (see FIGS. 3, 4 and5) and (S)-hydroxynorketamine (FIGS. 6, 7 and 8) are higher followingadministration of an OTF (see also Table 7 below) as compared tointravenous administration of 20 mg (S)-ketamine.

The plasma levels of ketamine are higher for intravenous administrationthan following administration of an OTF (see FIGS. 9, 10, 11 and Table 7below).

The examined film formulation is suitable for the treatment of pain.

TABLE 7 Cmax plasma concentration (ng/ml) All data All data SublinguallySublingually Buccally Buccally 50 mg 2 × 50 mg 50 mg 2 × 50 mg 50 mg 2 ×50 mg (S)-ketamine 101 143 95 138 117 158 (S)-Norketamine 254 330 258323 242 450 (S)-Hydroxynorketamine 94 171 98 173 81 165

Following the administration of a film, the plasma values to be achievedare preferably in the following ranges: cmax ((S)-ketamine)=50-200ng/mL; cmax ((S)-norketamine)=200-400 ng/mL; cmax((S)-hydroxynorketamine)=50-150 ng/mL.

If two films are administered, the plasma values to be achieved arepreferably in the following ranges: cmax ((S)-ketamine)=100-200 ng/mL;cmax ((S)-norketamine)=300-500 ng/mL; cmax (hydroxynorketamine)=100-250ng/mL.

Oral Bioavailability

The oral bioavailability for (S)-ketamine OTF is 26.3%±1.0%.

The oral bioavailability of 50 mg and 100 mg (S)-ketamine OTF differs byapproximately 20% (F1 50 mg=29%, F1 100 mg=23%), but this does not reachthe significance level (p»0.01).

Tmax, AUC data calculated using a PK model.

Data analysis of measured plasma concentrations of (S)-ketamine and itsmetabolites to determine a pharmacokinetic model was performed usingNONMEM version 7.5.0 (ICON Development Solutions, Hanover, Md., USA).

FOCI-I (first-order conditional estimation with interaction) was used tocalculate the pharmacokinetic model parameters. Based on the createdpharmacokinetic model, TMax data and AUC data of (S)-ketamine and itsmetabolites were calculated and are shown in Table 8.

TABLE 8 50 mg (S)-Ketamine OTF 100 mg (S)-Ketamine OTF (S)-Ketamin Tmax(min) 18.8 (16.6 - 21.2) 19.1 (17.1 - 21.2) AUC (0-6) 8.363 (7.263 -9.464) 13.347 (11.933 - 14.760) (ng/mL · min) (S)-Norketamine Tmax (min)61 (53-68) 78 (66-91) AUC (0-6) 38.497 (34.131 - 42.863) 67.959(60.045 - 75.872) (ng/mL · min) (S)-Hydroxynorketannine Tmax (min) 81(69-92) 109 (89 - 130) AUC (0-6) 24.087 (20.694 - 27.480) 44.972(38.563 - 51.382) (ng/mL · min)

Further results of the study are as follows:

1. The OTF formulation according to the invention has an analgesiceffect in all three pain modalities, irrespective of the localisation.

2. None of the used pain tests showed a clear dose-effect relationship.

3. In the electrical and thermal pain test, the analgesic effect islong-lasting and ranged from 2 to 6 hours, especially followingsub-lingual administration of the OTF.

4. There are no obvious differences in the data obtained during andafter sublingual and buccal administration.

5. The psychedelic effects for the administered OTF can be considered tobe very mild.

6. Eighteen (18) test subjects reported at least one adverse event. Intotal, there were 33 adverse events. None of these was a serious adverseevent (see Table 9 below for the prevalence of the events). The adverseevents were observed primarily for the intravenous administration of 20mg (S)-ketamine.

TABLE 9 20 mg (S)- 50 mg (S)- 100 mg (S)- ketamine Side effect ketamineketamine IV Blurred vision 1 — — Feeling of drunkenness 2 — —Bradykinesia 1 1 — Whistling noise in the ear — — 1 Dizziness 1 3 4Drowsiness — — 3 Nausea 1 1 2 Headache 1 2 3 Numbness of the tongue — 2— High blood pressure — — 2 (SBP>180mm Hg) Sweating — — 1 Dry eyes — — 1Total 7 9  17

The data relating to the observed psychedelic effects (psychological andpsychomimetic side effects) according to the Bowdle questionnaire aresummarised in FIGS. 12 to 15 and according to the Bond and Ladequestionnaire are summarised in FIGS. 16 to 31.

Example 5

The active agents R-ketamine and (S)-ketamine were compared.

To this end, oral thin films with the composition according to Table 10were produced.

TABLE 10 15 16 Material [wt. %] [wt. %] S ketamine HCl 60.0 — R-ketamineHCl 60.0 PVA 4-88 — — PVA 40-88 10.0 10.0 Kollicoat IR 20.1 20.1Saccharin Na 1.0 1.0 Sucralose 2.0 2.0 Glycerol 3.5 3.5 Cherry Flavour3.0 3.0 M55394 FD&C Red No, 40 0.4 0.4 Solvent Aq. Pur. Aq. Pur. Areadensity 215.73 g/m² 221.4 g/m²

The active agent flux was determined below in the in vitro model.

The active agent flux was performed within the scope of a typical invitro permeation by means of Franz diffusion cells (volume 10 mL) at 37°C. The used acceptor medium was replaced completely for a new one atpredetermined replacement times, and the content of permeated activeagent amount in these acceptor solutions was determined by means ofHPLC.

Phosphate buffer (pH 7.4) was used as acceptor medium.

Dermatomised skin from the oesophagus of a pig with a layer thickness of400 μm was used as skin model.

The results of the permeation study are shown in FIG. 32.

1. An oral thin film comprising at least one matrix layer, wherein theat least one matrix layer comprises at least one pharmaceutically activeagent, at least one polyvinyl alcohol, and at least one polyvinylalcohol-polyethylene glycol graft copolymer.
 2. The oral thin filmaccording to claim 1, wherein the at least one pharmaceutically activeagent comprises ketamine, preferably (S)-ketamine or a pharmaceuticallyacceptable salt thereof.
 3. The oral thin film according to claim 1,wherein the at least one pharmaceutically active agent is provided inthe matrix layer in an amount of 45 to 70 wt. % in relation to the totalweight of the matrix layer.
 4. The oral thin film according to claim 1,wherein the at least one polyvinyl alcohol comprises a polyvinyl alcoholwith a mean molecular weight of approximately 25,000 to approximately250,000 g/mol.
 5. The oral thin film according to claim 1, wherein theat least one polyvinyl alcohol comprises a polyvinyl alcohol with a meanmolecular weight of approximately 25,000 to approximately 35,000 g/moland/or a polyvinyl alcohol with a mean molecular weight of approximately200,000 to 210,000 g/mol.
 6. The oral thin film according to claim 1,wherein the at least one polyvinyl alcohol-polyethylene glycol graftcopolymer has a polyethylene glycol main chain onto which there aregrafted polyvinyl alcohol units.
 7. The oral thin film according toclaim 1, wherein the at least one polyvinyl alcohol-polyethylene glycolgraft copolymer has a polyethylene glycol main chain onto which thereare grafted polyvinyl alcohol units, wherein the molar ratio ofpolyethylene glycol to polyvinyl alcohol is 1:3.
 8. The oral thin filmaccording to claim 1, wherein the at least one polyvinylalcohol-polyethylene glycol graft copolymer has a polyethylene glycolmain chain onto which there are grafted polyvinyl alcohol units, whereinthe polyvinyl alcohol-polyethylene glycol graft copolymer has a meanmolecular weight in the range of 40,000 to 50,000 g/mol.
 9. The oralthin film according to claim 1, wherein the at least one polyvinylalcohol is provided in the matrix layer in an amount of 5 to 40 wt. % inrelation to the total weight of the matrix layer.
 10. The oral thin filmaccording to claim 1, wherein the at least one polyvinylalcohol-polyethylene glycol graft copolymer is provided in the matrixlayer in an amount of 15 to 45 wt. % in relation to the total weight ofthe matrix layer.
 11. The oral thin film according to claim 1, whereinthe oral thin film further comprises at least one auxiliary substanceselected from the group comprising colouring agents, flavourings,sweeteners, plasticisers, taste-masking agents, emulsifiers, enhancers,pH regulators, humectants, preservatives and/or antioxidants.
 12. Theoral thin film according to claim 1, wherein the area density of theoral thin film is approximately 50 to 300 g/m².
 13. The oral thin filmaccording to claim 1, wherein the at least one pharmaceutically activeagent comprises ketamine as a free base in a total amount of 25 to 150mg.
 14. The oral thin film according to claim 1, wherein at least 40% orat least 50% of the at least one pharmaceutically active agent arereleased within the first minute following application, and/or whereinat least 75% of the at least one pharmaceutically active agent arereleased within the first two minutes following application.
 15. Theoral thin film according to claim 1, wherein the puncture strength is atleast 0.15 N/mm², with an areal density of 150 to 250 g/m².
 16. The oralthin film according to claim 1, wherein the matrix layer comprises 60wt. % of (S)-ketamine HCl, 10 wt. % of a polyvinyl alcohol with a meanmolecular weight of approximately 200,000 to 210,000 g/mol, and 20.1 wt.% of a polyvinyl alcohol-polyethylene glycol graft copolymer, whereinthe polyvinyl alcohol-polyethylene glycol graft copolymer has apolyethylene glycol main chain onto which there are grafted polyvinylalcohol units, and wherein the polyvinyl alcohol-polyethylene glycolgraft copolymer has a mean molecular weight in the range of 40,000 to50,000 g/mol.
 17. The oral thin film according to claim 1, wherein themaximum plasma concentration of (S)-ketamine following administration ofa dose of 50 mg (S)-ketamine lies at 50 to 200 ng/mL, or wherein themaximum plasma concentration of (S)-ketamine following administration ofa dose of 100 mg (S)-ketamine lies at 100 to 200 ng/mL.
 18. The oralthin film according to claim 1, wherein the maximum plasma concentrationof the ketamine metabolite (S)-norketamine following administration of adose of 50 mg (S)-ketamine lies at 200 to 400 ng/mL, or wherein themaximum plasma concentration of the ketamine metabolite (S)-norketaminefollowing administration of a dose of 100 mg (S)-ketamine lies at 300 to500 ng/mL.
 19. The oral thin film according to claim 1, wherein themaximum plasma concentration of the ketamine metabolite(S)-hydroxynorketamine following administration of a dose of 50 mg(S)-ketamine lies at 50 to 150 ng/mL, or wherein the maximum plasmaconcentration of the ketamine metabolite (S)-hydroxynorketaminefollowing administration of a dose of 100 mg (S)-ketamine lies at 100 to250 ng/mL.
 20. A method for producing an oral thin film according toclaim 1, comprising the steps of: a) producing a solution, dispersion ormelt comprising the at least one pharmaceutically active agent, the atleast one polyvinyl alcohol and the at least one polyvinylalcohol-polyethylene glycol graft copolymer; a1) optionally foaming thesolution, dispersion or melt from step a) by introducing a gas or gasmixture, by chemical gas generation or by expansion of a dissolved gas,b) spreading the solution, dispersion or melt from step a) or theoptionally foamed solution, dispersion or melt from step a1.
 21. Amethod for the treatment of pain and/or depression comprising theadministration of an effective amount of the active agent included inthe oral thin film of claim 1.